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Melanoma: HELP
Articles by Jonathan Simon Cebon
Based on 62 articles published since 2008
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Between 2008 and 2019, J. S. Cebon wrote the following 62 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Evolving role of tumor antigens for future melanoma therapies. 2014

Andrews, Miles C / Woods, Katherine / Cebon, Jonathan / Behren, Andreas. ·Ludwig Institute for Cancer Research Ltd, Olivia Newton-John Cancer & Wellness Centre, Cancer Immunobiology, Heidelberg, VIC, Australia. ·Future Oncol · Pubmed #25052755.

ABSTRACT: Human tumor rejection antigens recognized by T lymphocytes were first defined in the early 1990s and the identification of shared tumor-restricted antigens sparked hopes for the development of a therapeutic vaccination to treat cancer, including melanoma. Despite decades of intense preclinical and clinical research, the success of anticancer vaccines based on these antigens has been limited. While melanoma is a highly immunogenic tumor, the ability to prime immunity with vaccines has not generally translated into objective disease regression. However, with the development of small molecules targeting oncogenic proteins, such as V600-mutated BRAF, and immune checkpoint inhibitors with demonstrable long-lasting clinical benefit, new opportunities for antigen-targeted directed therapies are emerging.

2 Review Immune consequences of kinase inhibitors in development, undergoing clinical trials and in current use in melanoma treatment. 2014

Vella, Laura J / Andrews, Miles C / Behren, Andreas / Cebon, Jonathan / Woods, Katherine. ·Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immuno-biology Laboratory, Heidelberg, VIC 3084, Australia. ·Expert Rev Clin Immunol · Pubmed #24939732.

ABSTRACT: Metastatic malignant melanoma is a frequently fatal cancer. In recent years substantial therapeutic progress has occurred with the development of targeted kinase inhibitors and immunotherapeutics. Targeted therapies often result in rapid clinical benefit however responses are seldom durable. Immune therapies can result in durable disease control but responses may not be immediate. Optimal cancer therapy requires both rapid and durable cancer control and this can likely best be achieved by combining targeted therapies with immunotherapeutics. To achieve this, a detailed understanding of the immune consequences of the various kinase inhibitors, in development, clinical trial and currently used to treat melanoma is required.

3 Review Melanoma vaccines: developments over the past 10 years. 2011

Klein, Oliver / Schmidt, Christopher / Knights, Ashley / Davis, Ian D / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research, Austin Branch, Austin Hospital, Studley Road, Heidelberg, Victoria, 3084, Australia. ·Expert Rev Vaccines · Pubmed #21692705.

ABSTRACT: Decades of preclinical evaluation and clinical trials into melanoma vaccines have yielded spectacular progress in our understanding of melanoma antigens and the immune mechanisms of tumor rejection. Key insights and the results of their clinical evaluation are reviewed in this article. Unfortunately, durable clinical benefit following vaccination remains uncommon. Two recent clinical advances that will impact on melanoma vaccine development are trials with inhibitors of CTLA-4 and oncogenic BRAF. Long-term therapeutic control of melanoma will require integration of specific active immunotherapy with these emerging successful therapies from the disparate fields of immune regulation and signal transduction.

4 Clinical Trial Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma. 2017

Petrella, Teresa M / Robert, Caroline / Richtig, Erika / Miller, Wilson H / Masucci, Giuseppe V / Walpole, Euan / Lebbe, Celeste / Steven, Neil / Middleton, Mark R / Hille, Darcy / Zhou, Wei / Ibrahim, Nageatte / Cebon, Jonathan. ·Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, T2-041, Toronto, ON, M4N 3M5, Canada. Electronic address: teresa.petrella@sunnybrook.ca. · Gustave Roussy and Université Paris-Sud, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: caroline.robert@gustaveroussy.fr. · Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Graz, Austria. Electronic address: erika.richtig@medunigraz.at. · Segal Cancer Centre, Jewish General Hospital, Rossy Cancer Network, and McGill University, 3755 Ch de la Côte-Sainte-Catherine, Montreal, QC, H3T 1E2, Canada. Electronic address: wilsonmiller@gmail.com. · Karolinska Institute, Solnavägen 1, 171 77 Solna, Stockholm, Sweden. Electronic address: giuseppe.masucci@ki.se. · Princess Alexandra Hospital and The University of Queensland, 199 Ipswich Rd, Woolloongabba, Brisbane, QLD 4102, Australia. Electronic address: euan.walpole@health.qld.gov.au. · APHP, Dermatology and CIC, Université Paris Diderot, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France. Electronic address: celeste.lebbe@aphp.fr. · Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2TH, UK. Electronic address: N.M.Steven@bham.ac.uk. · The Churchill Hospital and The University of Oxford, Old Rd, Headington, Oxford OX3 7LE, UK. Electronic address: mark.middleton@oncology.ox.ac.uk. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: darcy_hille@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: wei.zhou2@merck.com. · Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: nageatte.ibrahim@merck.com. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, La Trobe University, 145 Studley Road, Heidelberg VIC 3084, Melbourne, Australia. Electronic address: jonathan.cebon@onjcri.org.au. ·Eur J Cancer · Pubmed #28987768.

ABSTRACT: OBJECTIVE: Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma. PATIENTS AND METHODS: Patients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis. RESULTS: The PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of -1.9 and -2.5 for pembrolizumab versus -10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales. CONCLUSIONS: HRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01866319.

5 Clinical Trial Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. 2017

Wolchok, Jedd D / Chiarion-Sileni, Vanna / Gonzalez, Rene / Rutkowski, Piotr / Grob, Jean-Jacques / Cowey, C Lance / Lao, Christopher D / Wagstaff, John / Schadendorf, Dirk / Ferrucci, Pier F / Smylie, Michael / Dummer, Reinhard / Hill, Andrew / Hogg, David / Haanen, John / Carlino, Matteo S / Bechter, Oliver / Maio, Michele / Marquez-Rodas, Ivan / Guidoboni, Massimo / McArthur, Grant / Lebbé, Celeste / Ascierto, Paolo A / Long, Georgina V / Cebon, Jonathan / Sosman, Jeffrey / Postow, Michael A / Callahan, Margaret K / Walker, Dana / Rollin, Linda / Bhore, Rafia / Hodi, F Stephen / Larkin, James. ·From the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W., M.A.P., M.K.C.) · Oncology Institute of Veneto Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua (V.C.-S.), European Institute of Oncology, Milan (P.F.F.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M.M.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · University of Colorado, Denver (R.G.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Aix-Marseille University, Hôpital de la Timone, Marseille (J.-J.G.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint-Louis, Université Paris Diderot, Paris (C.L.) - both in France · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · University of Michigan, Ann Arbor (C.D.L.) · the College of Medicine, Swansea University, Swansea (J.W.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.) · Cross Cancer Institute, Edmonton, AB (M.S.), and Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada · Universitäts Spital, Zurich, Switzerland (R.D.) · Tasman Oncology Research, Southport Gold Coast, QLD (A.H.), Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney (M.S.C.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and Peter MacCallum Cancer Centre (G.M.) and the Olivia Newton-John Cancer Research Institute, University of Melbourne (J.C.), Melbourne, VIC - all in Australia · Netherlands Cancer Institute, Amsterdam (J.H.) · University Hospitals Leuven, KU Leuven, Leuven, Belgium (O.B.) · General University Hospital Gregorio Marañón, Madrid (I.M.-R.) · Northwestern University, Chicago (J.S.) · Bristol-Myers Squibb, Princeton, NJ (D.W., L.R., R.B.) · and the Dana-Farber Cancer Institute, Boston (F.S.H.). ·N Engl J Med · Pubmed #28889792.

ABSTRACT: BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

6 Clinical Trial Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. 2017

Ribas, Antoni / Dummer, Reinhard / Puzanov, Igor / VanderWalde, Ari / Andtbacka, Robert H I / Michielin, Olivier / Olszanski, Anthony J / Malvehy, Josep / Cebon, Jonathan / Fernandez, Eugenio / Kirkwood, John M / Gajewski, Thomas F / Chen, Lisa / Gorski, Kevin S / Anderson, Abraham A / Diede, Scott J / Lassman, Michael E / Gansert, Jennifer / Hodi, F Stephen / Long, Georgina V. ·University of California at Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · University Hospital of Zurich, Zurich, Switzerland. · Roswell Park Cancer Institute, Buffalo, NY, USA. · The West Clinic, Memphis, TN, USA. · University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA. · Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · Fox Chase Cancer Center, Philadelphia, PA, USA. · Hospital Clinic i Provincial de Barcelona, Barcelona, Spain. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Hopitaux Universitaires de Genève, Geneva, Switzerland. · University of Pittsburgh Cancer Institute and Hillman UPMC Cancer Center, Pittsburgh, PA, USA. · The University of Chicago School of Medicine, Chicago, IL, USA. · Amgen Inc., Thousand Oaks, CA, USA. · Amgen Inc., South San Francisco, CA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, The University of Sydney and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia. ·Cell · Pubmed #28886381.

ABSTRACT: Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8

7 Clinical Trial Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. 2017

Long, Georgina V / Atkinson, Victoria / Cebon, Jonathan S / Jameson, Michael B / Fitzharris, Bernie M / McNeil, Catriona M / Hill, Andrew G / Ribas, Antoni / Atkins, Michael B / Thompson, John A / Hwu, Wen-Jen / Hodi, F Stephen / Menzies, Alexander M / Guminski, Alexander D / Kefford, Richard / Kong, Benjamin Y / Tamjid, Babak / Srivastava, Archana / Lomax, Anna J / Islam, Mohammed / Shu, Xinxin / Ebbinghaus, Scot / Ibrahim, Nageatte / Carlino, Matteo S. ·Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. Electronic address: georgina.long@sydney.edu.au. · Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD, Australia; University of Queensland, Brisbane, QLD, Australia. · Olivia Newton-John Cancer Research Institute, Austin Health, School of Cancer Medicine, LaTrobe University, Heidelberg, VIC, Australia. · Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. · Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand. · Royal Prince Alfred Hospital, Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Chris O'Brien Lifehouse, Camperdown, NSW, Australia. · Tasman Oncology Research, Southport Gold Coast, QLD, Australia. · Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. · Department of Medicine, University of Washington, Seattle, WA, USA. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Melanoma Institute Australia, University of Sydney, Mater Hospital, Sydney, NSW, Australia; Royal North Shore Hospital, Sydney, NSW, Australia. · Westmead Hospital, Melanoma Institute Australia, Macquarie University, Sydney, NSW, Australia. · Westmead Hospital, Westmead, NSW, Australia; Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia; Blacktown Hospital, Blacktown, NSW, Australia. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Oncol · Pubmed #28729151.

ABSTRACT: BACKGROUND: Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose pembrolizumab in combination with reduced-dose ipilimumab. METHODS: In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. FINDINGS: Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8-18·8). 110 (72%) of 153 patients received all four pembrolizumab plus ipilimumab doses; 64 (42%) remained on pembrolizumab monotherapy. 110 grade 3-4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3-4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53-69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60-75), and estimated 1 year overall survival was 89% (95% CI 83-93). INTERPRETATION: Standard-dose pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. FUNDING: Merck & Co, Inc.

8 Clinical Trial Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. 2016

Long, Georgina V / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Daud, Adil / Gonzalez, Rene / Sosman, Jeffrey A / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Kefford, Richard F / Lawrence, Donald / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Puzanov, Igor / Ibrahim, Nageatte / Sun, Peng / Cunningham, Elizabeth / Kline, Amy S / Del Buono, Heather / McDowell, Diane Opatt / Patel, Kiran / Flaherty, Keith T. ·Georgina V. Long, Melanoma Institute Australia · The University of Sydney · Richard F. Kefford, Melanoma Institute Australia · The University of Sydney · Macquarie University, Sydney · Westmead Hospital, Westmead · Jonathan Cebon, Austin Health, Melbourne, Victoria, Australia · Jeffrey S. Weber and Ragini Kudchadkar, Moffitt Cancer Center, Tampa, FL · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute/Tennessee Oncology · Kevin B. Kim, California Pacific Medical Center · Adil Daud, Alain Algazi, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, Karl Lewis, University of Colorado · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Jeffrey A. Sosman, Igor Puzanov, Vanderbilt University Medical Center, Nashville, TN · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Elizabeth Cunningham, Merck · Peng Sun, Amy S. Kline, Heather Del Buono, Diane Opatt McDowell, GlaxoSmithKline, Philadelphia, PA · Donald Lawrence and Kiran Patel, Incyte Corporation, Wilmington, DE · and Keith T. Flaherty, Massachusetts General Hospital Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #26811525.

ABSTRACT: PURPOSE: To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma. METHODS: BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS. RESULTS: For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response. CONCLUSION: Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

9 Clinical Trial First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors. 2016

Dienstmann, Rodrigo / Lassen, Ulrik / Cebon, Jonathan / Desai, Jayesh / Brown, Michael P / Evers, Stefan / Su, Fei / Zhang, Weijiang / Boisserie, Frederic / Lestini, Brian / Schostack, Kathleen / Meresse, Valerie / Tabernero, Josep. ·Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. rdienstmann@vhio.net. · , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rdienstmann@vhio.net. · Department of Oncology, Rigshospitalet, Copenhagen, Denmark. · Austin Hospital, Oncology Unit, Heidelberg, Australia. · Royal Melbourne Hospital, Parkville, Australia. · Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia. · Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. · Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA. · Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. · Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA. · Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ, USA. · Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland. · Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. jtabernero@vhio.net. · , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. jtabernero@vhio.net. ·Target Oncol · Pubmed #26310975.

ABSTRACT: BACKGROUND: BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors. PATIENTS AND METHODS: Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design. RESULTS: In total, 45 patients were enrolled; most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor samples. CONCLUSIONS: RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent. Study Identifier: ClinicalTrials.gov (NCT01143753).

10 Clinical Trial Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma. 2015

Klein, Oliver / Davis, Ian D / McArthur, Grant A / Chen, Li / Haydon, Andrew / Parente, Phillip / Dimopoulos, Nektaria / Jackson, Heather / Xiao, Kun / Maraskovsky, Eugene / Hopkins, Wendie / Stan, Rodica / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research (Melbourne-Austin Branch), 147-163 Studley Road, Heidelberg, VIC, 3084, Australia, oliver.klein@ludwig.edu.au. ·Cancer Immunol Immunother · Pubmed #25662405.

ABSTRACT: Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4(+) T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.

11 Clinical Trial Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. 2014

Johnson, Douglas B / Flaherty, Keith T / Weber, Jeffrey S / Infante, Jeffrey R / Kim, Kevin B / Kefford, Richard F / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William H / McWilliams, Robert R / Sznol, Mario / Lawrence, Donald P / Gibney, Geoffrey T / Burris, Howard A / Falchook, Gerald S / Algazi, Alain / Lewis, Karl / Long, Georgina V / Patel, Kiran / Ibrahim, Nageatte / Sun, Peng / Little, Shonda / Cunningham, Elizabeth / Sosman, Jeffrey A / Daud, Adil / Gonzalez, Rene. ·Douglas B. Johnson and Jeffrey A. Sosman, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center · Jeffrey R. Infante and Howard A. Burris III, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN · Keith T. Flaherty and Donald P. Lawrence, Massachusetts General Hospital Cancer Center, Boston MA · Jeffrey S. Weber and Geoffrey T. Gibney, Moffitt Cancer Center, Tampa, FL · Kevin B. Kim and Gerald S. Falchook, University of Texas MD Anderson Cancer Center, Houston, TX · Richard F. Kefford and Georgina V. Long, Melanoma Institute Australia, University of Sydney and Westmead Hospital, Sydney, New South Wales · Jonathan Cebon, Joint Ludwig-Austin Oncology Unit, Austin Health, Melbourne, Victoria, Australia · Omid Hamid, Angeles Clinic and Research Institute, Los Angeles · Alain Algazi and Adil Daud, University of California, San Francisco, San Francisco, CA · Lynn Schuchter, University of Pennsylvania Abramson Cancer Center · Nageatte Ibrahim, Peng Sun, Shonda Little, and Elizabeth Cunningham, GlaxoSmithKline, Philadelphia, PA · William H. Sharfman, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD · Robert R. McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT · Karl Lewis and Rene Gonzalez, University of Colorado, Denver, CO · and Kiran Patel, Incyte, Wilmington, DE. ·J Clin Oncol · Pubmed #25287827.

ABSTRACT: PURPOSE: Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. PATIENTS AND METHODS: In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). RESULTS: In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). CONCLUSION: Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

12 Clinical Trial A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma. 2012

Ebert, Lisa M / MacRaild, Sarah E / Zanker, Damien / Davis, Ian D / Cebon, Jonathan / Chen, Weisan. ·Ludwig Institute for Cancer Research (Melbourne-Austin Branch), Melbourne, Australia. ·PLoS One · Pubmed #23110239.

ABSTRACT: Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIX™ cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1-specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials.

13 Clinical Trial Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. 2012

Flaherty, Keith T / Infante, Jeffery R / Daud, Adil / Gonzalez, Rene / Kefford, Richard F / Sosman, Jeffrey / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Ibrahim, Nageatte / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald / Algazi, Alain / Lewis, Karl / Long, Georgina V / Puzanov, Igor / Lebowitz, Peter / Singh, Ajay / Little, Shonda / Sun, Peng / Allred, Alicia / Ouellet, Daniele / Kim, Kevin B / Patel, Kiran / Weber, Jeffrey. ·Massachusetts General Hospital Cancer Center, Boston, USA. ·N Engl J Med · Pubmed #23020132.

ABSTRACT: BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

14 Clinical Trial Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. 2009

Klein, Oliver / Ebert, Lisa M / Nicholaou, Theo / Browning, Judy / Russell, Sarah E / Zuber, Marina / Jackson, Heather M / Dimopoulos, Nektaria / Tan, Bee Shin / Hoos, Axel / Luescher, Immanuel F / Davis, Ian D / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Heidelberg, Victoria, Australia. ·Clin Cancer Res · Pubmed #19318477.

ABSTRACT: PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy.

15 Clinical Trial Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. 2009

Nicholaou, Theo / Ebert, Lisa M / Davis, Ian D / McArthur, Grant A / Jackson, Heather / Dimopoulos, Nektaria / Tan, Bee / Maraskovsky, Eugene / Miloradovic, Lena / Hopkins, Wendie / Pan, Linda / Venhaus, Ralph / Hoffman, Eric W / Chen, Weisan / Cebon, Jonathan. ·Ludwig Institute for Cancer Research, Austin Health, Peter MacCallum Cancer Centre, CSL Limited, Melbourne, Victoria, Australia. ·Clin Cancer Res · Pubmed #19276262.

ABSTRACT: PURPOSE: NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma. EXPERIMENTAL DESIGN: Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients. RESULTS: In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease. CONCLUSIONS: Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.

16 Clinical Trial Clinical and biological efficacy of recombinant human interleukin-21 in patients with stage IV malignant melanoma without prior treatment: a phase IIa trial. 2009

Davis, Ian D / Brady, Ben / Kefford, Richard F / Millward, Michael / Cebon, Jonathan / Skrumsager, Birte K / Mouritzen, Ulrik / Hansen, Lasse Tengbjerg / Skak, Kresten / Lundsgaard, Dorthe / Frederiksen, Klaus Stensgaard / Kristjansen, Paul E G / McArthur, Grant. ·Ludwig Oncology Unit, Austin Health, Melbourne, Victoria, Australia. ·Clin Cancer Res · Pubmed #19276257.

ABSTRACT: PURPOSE: Human interleukin-21 (IL-21) is a class I cytokine that mediates activation of CD8(+) T cells, natural killer (NK) cells, and other cell types. We report final clinical and biological results of a phase II study of recombinant human IL-21 (rIL-21) in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Open-label, single-arm, two-stage trial. ELIGIBILITY CRITERIA: unresectable metastatic melanoma, measurable disease by Response Evaluation Criteria in Solid Tumors, no prior systemic therapy (adjuvant IFN permitted), adequate major organ function, good performance status, no significant autoimmune disease, and life expectancy at least 4 months. PRIMARY OBJECTIVE: antitumor efficacy (response rate). SECONDARY OBJECTIVES: safety, blood biomarkers, and generation of anti-rIL-21 antibodies. rIL-21 (30 microg/kg/dose) was administered by intravenous bolus injection in 8-week cycles (5 dosing days followed by 9 days of rest for 6 weeks and then 2 weeks off treatment). RESULTS: Stage I of the study comprised 14 patients. One confirmed complete response (CR) was observed, and as per protocol, 10 more patients were accrued to stage II (total n = 24: 10 female and 14 male). Best tumor response included one confirmed CR and one confirmed partial response, both with lung metastases. Treatment was overall well tolerated. Biomarker analyses showed increases in serum soluble CD25, frequencies of CD25(+) NK and CD8(+) T cells, and mRNA for IFN-gamma, perforin, and granzyme B in CD8(+) T and NK cells. CONCLUSIONS: rIL-21 administered at 30 microg/kg/d in 5-day cycles every second week is biologically active and well tolerated in patients with metastatic melanoma. Confirmed responses, including one CR, were observed.

17 Article Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. 2019

Parakh, Sagun / Randhawa, Manreet / Nguyen, Bella / Warburton, Lydia / Hussain, Mohammad Akhtar / Cebon, Jonathan / Millward, Michael / Yip, Desmond / Ali, Sayed. ·Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia. · La Trobe University School of Cancer Medicine, Melbourne, Victoria, Australia. · Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, ACT, Australia. · Department of Medical Oncology, Sir Charles Gairdner Hospital, WA, Australia. · Western Australia Centre for Rural Health, University of Western Australia, WA, Australia. · School of Population and Global Health, University of Western Australia, WA, Australia. · ANU Medical School, Australian National University, ACT, Australia. ·Asia Pac J Clin Oncol · Pubmed #30426665.

ABSTRACT: BACKGROUND: There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab. METHOD: We retrospectively identified patients (pts) with metastatic melanoma treated with three-weekly nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) for four cycles followed by nivolumab monotherapy (3 mg/kg) fortnightly. Patient demographics and treatment parameters were collected and outcomes determined. RESULTS: A total of 45 pts received combination treatment with a median follow up of 8.7 months (range 0.33-25.9 months). A total of 67% were male, and BRAF V600 mutations detected in 38%. At treatment commencement, 14 (31%) pts had brain metastases, 51% had an elevated LDH and 18 (40%) were treatment-naive. Almost a third (30%) required corticosteroids for symptom control or management of prior toxicities. Nineteen (42%) patients had prior anti-PD-1 therapy. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment naïve patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts. CONCLUSION: In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-naïve pts. The toxicity profile seen in this study is similar to those reported in clinical trials.

18 Article Neutrophil to lymphocyte ratio is an independent predictor of outcome for patients undergoing definitive resection for stage IV melanoma. 2018

Kanatsios, Stefanos / Melanoma Project, Melbourne / Li Wai Suen, Connie S N / Cebon, Jonathan Simon / Gyorki, David E. ·Austin Health, Heidelberg, VIC, Australia. · Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia. · University of Melbourne, Parkville, VIC, Australia. · Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. ·J Surg Oncol · Pubmed #30196539.

ABSTRACT: BACKGROUND AND OBJECTIVES: The aim of this study was to perform a retrospective analysis of survival rates and determine prognostic indicators for patients who underwent definitive surgical resection of stage IV melanoma. METHODS: Patients included were those who underwent complete resection of metastatic melanoma. Data was analyzed using IBM SPSS 2.0. Survival estimates were derived from Kaplan-Meier, log-rank, and Breslow tests. RESULTS: The study population (n = 95) consisted of 60 males and 35 females. Median overall survival (OS) from the first metastasectomy was 49 months (95% confidence interval, 31-67 months). OS at 1, 2, and 5 years was 92%, 87%, and 50% respectively. Predictors of survival included clear surgical margins compared to patients with positive margins (median OS 53 vs 20 months, P = .026). A preoperative neutrophil to lymphocyte ratio less than 5 experienced a median OS of 65 months compared to 15 months ( P = .006; multivariable analysis for OS: hazard ratio 3.590, P = .009). CONCLUSION: This study's results are consistent with previous findings demonstrating favourable long-term outcomes following selective resection of metastatic melanoma. In addition to achieving clear surgical margins, a low preoperative neutrophil to lymphocyte ratio was associated with improved outcomes. These factors may help identify surgical candidates.

19 Article Characterising the phenotypic evolution of circulating tumour cells during treatment. 2018

Tsao, Simon Chang-Hao / Wang, Jing / Wang, Yuling / Behren, Andreas / Cebon, Jonathan / Trau, Matt. ·Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. · Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. · Department of Surgery, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia. · Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. yuling.wang@mq.edu.au. · Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, 2109, Australia. yuling.wang@mq.edu.au. · School of Cancer Medicine, La Trobe University, Bundoora, VIC, 3086, Australia. · Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, 4072, Australia. m.trau@uq.edu.au. · School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD, 4072, Australia. m.trau@uq.edu.au. ·Nat Commun · Pubmed #29662054.

ABSTRACT: Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

20 Article Intercellular Resistance to BRAF Inhibition Can Be Mediated by Extracellular Vesicle-Associated PDGFRβ. 2017

Vella, Laura J / Behren, Andreas / Coleman, Bradley / Greening, David W / Hill, Andrew F / Cebon, Jonathan. ·Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; The Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: ljvella@unimelb.edu.au. · Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Heidelberg. · Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia. ·Neoplasia · Pubmed #28963969.

ABSTRACT: Treatment of BRAF mutant melanoma with kinase inhibitors has been associated with rapid tumor regression; however, this clinical benefit is short-lived, and most patients relapse. A number of studies suggest that the extracellular environment promotes BRAF inhibitor resistance and tumor progression. Extracellular vesicles, such as exosomes, are functional mediators in the extracellular environment. They are small vesicles known to carry a concentrated group of functional cargo and serve as intercellular communicators not only locally but also systemically. Increasingly, it is reported that extracellular vesicles facilitate the development of drug resistance in cancer; however, their role in BRAF inhibitor resistance in melanoma is unclear. Here we investigated if extracellular vesicles from BRAF inhibitor-resistant melanoma could influence drug sensitivity in recipient melanoma cells. We demonstrate that the resistance driver, PDGFRβ, can be transferred to recipient melanoma cells via extracellular vesicles, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from MAPK pathway BRAF inhibition. These data suggest that the BRAF inhibitor-sensitive phenotype of metastatic melanoma can be altered by delivery of PDGFRβ by extracellular vesicles derived from neighboring drug-resistant melanoma cells.

21 Article Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. 2017

Sznol, Mario / Ferrucci, Pier Francesco / Hogg, David / Atkins, Michael B / Wolter, Pascal / Guidoboni, Massimo / Lebbé, Celeste / Kirkwood, John M / Schachter, Jacob / Daniels, Gregory A / Hassel, Jessica / Cebon, Jonathan / Gerritsen, Winald / Atkinson, Victoria / Thomas, Luc / McCaffrey, John / Power, Derek / Walker, Dana / Bhore, Rafia / Jiang, Joel / Hodi, F Stephen / Wolchok, Jedd D. ·Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Pier Francesco Ferrucci, Istituto Europeo di Oncologia, Milan · Massimo Guidoboni, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy · David Hogg, Princess Margaret Cancer Centre, Toronto, Ontario, Canada · Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC · Pascal Wolter, University Hospitals Leuven, Leuven, Belgium · Celeste Lebbé, Université Paris Diderot, Paris · Luc Thomas, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France · John M. Kirkwood, Hillman Cancer Center, Pittsburgh, PA · Jacob Schachter, Sheba Medical Center, Ramat Gan, Israel · Gregory A. Daniels, University of California San Diego, Moores Cancer Center, La Jolla, CA · Jessica Hassel, University Hospital, Heidelberg, Germany · Jonathan Cebon, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria · Winald Gerritsen, University of Queensland, St Lucia · Victoria Atkinson, Gallipoli Medical Research Foundation, Greenslopes · Victoria Atkinson, Princess Alexandra Hospital, Brisbane, Queensland, Australia · Winald Gerritsen, Radboud University Medical Center, Nijmegen, the Netherlands · John McCaffrey, Irish Clinical Oncology Research Group, Dublin · Derek Power, Irish Clinical Oncology Research Group, Cork, Ireland · Dana Walker, Rafia Bhore, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ · F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA · and Jedd D. Wolchok, Parker Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY. ·J Clin Oncol · Pubmed #28915085.

ABSTRACT: Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

22 Article Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases. 2017

Parakh, Sagun / Park, John J / Mendis, Shehara / Rai, Rajat / Xu, Wen / Lo, Serigne / Drummond, Martin / Rowe, Catherine / Wong, Annie / McArthur, Grant / Haydon, Andrew / Andrews, Miles C / Cebon, Jonathan / Guminski, Alex / Kefford, Richard F / Long, Georgina V / Menzies, Alexander M / Klein, Oliver / Carlino, Matteo S. ·Medical Oncology Unit, Austin Health, Melbourne, Victoria 3084, Australia. · Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia. · La Trobe University School of Cancer Medicine, Melbourne, Victoria 3086, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales 2145, Australia. · The University of Sydney, Sydney, New South Wales 2006, Australia. · Medical Oncology Unit, Alfred Hospital, Melbourne, Victoria 3004, Australia. · Melanoma Institute Australia, Sydney, New South Wales 2060, Australia. · Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. · Royal North Shore and Mater Hospitals, Sydney, New South Wales 2065, Australia. · Department of Clinical Medicine, Macquarie University, New South Wales 2109, Australia. ·Br J Cancer · Pubmed #28524161.

ABSTRACT: BACKGROUND: There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic. METHOD: We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039). CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

23 Article Whole-genome landscapes of major melanoma subtypes. 2017

Hayward, Nicholas K / Wilmott, James S / Waddell, Nicola / Johansson, Peter A / Field, Matthew A / Nones, Katia / Patch, Ann-Marie / Kakavand, Hojabr / Alexandrov, Ludmil B / Burke, Hazel / Jakrot, Valerie / Kazakoff, Stephen / Holmes, Oliver / Leonard, Conrad / Sabarinathan, Radhakrishnan / Mularoni, Loris / Wood, Scott / Xu, Qinying / Waddell, Nick / Tembe, Varsha / Pupo, Gulietta M / De Paoli-Iseppi, Ricardo / Vilain, Ricardo E / Shang, Ping / Lau, Loretta M S / Dagg, Rebecca A / Schramm, Sarah-Jane / Pritchard, Antonia / Dutton-Regester, Ken / Newell, Felicity / Fitzgerald, Anna / Shang, Catherine A / Grimmond, Sean M / Pickett, Hilda A / Yang, Jean Y / Stretch, Jonathan R / Behren, Andreas / Kefford, Richard F / Hersey, Peter / Long, Georgina V / Cebon, Jonathan / Shackleton, Mark / Spillane, Andrew J / Saw, Robyn P M / López-Bigas, Núria / Pearson, John V / Thompson, John F / Scolyer, Richard A / Mann, Graham J. ·Melanoma Institute Australia, The University of Sydney, North Sydney, Sydney, New South Wales 2065, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. · Discipline of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. · Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia. · Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. · Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain. · Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain. · Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, Sydney, New South Wales 2145, Australia. · Children's Hospital at Westmead, The University of Sydney, Westmead, New South Wales Sydney, 2145, Australia. · Bioplatforms Australia, North Ryde, Sydney, New South Wales 2109, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Parkville, Melbourne, Victoria 3052, Australia. · School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales 2006, Australia. · Olivia Newton-John Cancer Research Institute, La Trobe University, Austin Health, Heidelberg, Melbourne, Victoria 3084, Australia. · Macquarie University, North Ryde, Sydney, New South Wales 2109, Australia. · Centenary Institute, The University of Sydney, Sydney, New South Wales 2006, Australia. · Department of Medical Oncology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria 3000, Australia. · Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia. ·Nature · Pubmed #28467829.

ABSTRACT: Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

24 Article Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists. 2016

Atkinson, Victoria / Long, Georgina V / Menzies, Alexander M / McArthur, Grant / Carlino, Matteo S / Millward, Michael / Roberts-Thomson, Rachel / Brady, Benjamin / Kefford, Richard / Haydon, Andrew / Cebon, Jonathan. ·Princess Alexandra Hospital, Greenslopes Private Hospital and University of Queensland, Brisbane, Queensland, Australia. · Melanoma Institute Australia, Royal North Shore and Mater Hospitals, The University of Sydney, Sydney, New South Wales, Australia. · Peter MacCallum Cancer Centre and Cabrini Health, Melbourne, Victoria, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · School of Medicine and Pharmacology, University of Western Australia and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. · Queen Elizabeth Hospital, Adelaide, South Australia, Australia. · Westmead Hospital and Macquarie University, Sydney, New South Wales, Australia. · The Alfred Hospital, Melbourne, Victoria, Australia. · Olivia Newton John Cancer Wellness & Research Centre, Austin Health Melbourne, Victoria, Australia. ·Asia Pac J Clin Oncol · Pubmed #27905182.

ABSTRACT: BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

25 Article Systems analysis identifies miR-29b regulation of invasiveness in melanoma. 2016

Andrews, Miles C / Cursons, Joseph / Hurley, Daniel G / Anaka, Matthew / Cebon, Jonathan S / Behren, Andreas / Crampin, Edmund J. ·Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. · Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, 3084, Australia. · School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. · Department of Medicine, University of Melbourne, Parkville, VIC, 3010, Australia. · Systems Biology Laboratory, University of Melbourne, Parkville, VIC, 3010, Australia. · ARC Centre of Excellence in Convergent Bio-Nano Science, University of Melbourne, Parkville, VIC, 3010, Australia. · School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, 3010, Australia. · Centre for Systems Genomics, University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Medicine, University of Toronto, Toronto, ON, Canada. · Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. jonathan.cebon@onjcri.org.au. · Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, 3084, Australia. jonathan.cebon@onjcri.org.au. · School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. jonathan.cebon@onjcri.org.au. · Department of Medicine, University of Melbourne, Parkville, VIC, 3010, Australia. jonathan.cebon@onjcri.org.au. · Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia. andreas.behren@onjcri.org.au. · Ludwig Institute for Cancer Research, Melbourne-Austin Branch, Cancer Immunobiology Laboratory, Heidelberg, VIC, 3084, Australia. andreas.behren@onjcri.org.au. · School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. andreas.behren@onjcri.org.au. · Department of Medicine, University of Melbourne, Parkville, VIC, 3010, Australia. edmund.crampin@unimelb.edu.au. · Systems Biology Laboratory, University of Melbourne, Parkville, VIC, 3010, Australia. edmund.crampin@unimelb.edu.au. · ARC Centre of Excellence in Convergent Bio-Nano Science, University of Melbourne, Parkville, VIC, 3010, Australia. edmund.crampin@unimelb.edu.au. · School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, 3010, Australia. edmund.crampin@unimelb.edu.au. · Centre for Systems Genomics, University of Melbourne, Parkville, VIC, 3010, Australia. edmund.crampin@unimelb.edu.au. ·Mol Cancer · Pubmed #27852308.

ABSTRACT: BACKGROUND: In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. METHODS: We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson's correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines - the Ludwig Melbourne melanoma (LM-MEL) cell line panel - we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. RESULTS: Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, -221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. CONCLUSIONS: This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner.

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